Epidemiological studies have not consistently linked any specific dietary component to either an increased or reduced breast cancer risk. We propose that this is partly due to the incomplete consideration that timing of dietary exposures might be more important in affecting the risk than an exposure shortly before or at diagnosis. We further propose that the breast is most sensitive to dietary factors at times when diet-induced biological changes can alter its development and function. These sensitive periods include fetal life, puberty, and pregnancy, when the breast undergoes extensive proliferation following a natural exposure to high levels of hormones and growth factors. Steroid hormones and their nuclear receptors are known to play a central role in breast cancer. In this U54 program, we will focus on studying the timing of exposures to nutritional components that interact with nuclear hormone receptors. In three first Projects (P-I to P-Ill) by Drs. Hilakivi-Clarke (P-I), Byers (P-II) and Makela (P-Ill), we will explore whether timing of dietary exposures to phytoestrogens, n-3 polyunsaturated fatty acids and vitamins A and D alter mammary tumorigenesis and the mechanisms mediating these associations. The mechanisms include changes in estrogen receptor (ER) a and ERb, BRCA1, cyclin D1, and b-catenin. Animal models that mimic both sporadic and familial breast cancers will be used. The projects will interact with each other in several fronts. Two epidemiological projects by Drs. Nevanlinna and Luoto (P-IV) and Dr. Fogelholm (Pilot I) will examine whether timing of excessive energy intake affects the risk of developing familiar breast cancer, and whether dietary intervention to prevent excessive weight gain during pregnancy reduces breast cancer risk. The epidemiological projects will interact with P-I and Pilot II. Pilot II by Dr. Martin will study the role of ERa in mediating the effects of selenium on the breast. Three core facilities are also included: Administrative Core, Biostatistics and Microarray Core, and Bioresources Core. This program aims to develop novel means to prevent some breast cancers by dietary modifications that take place during pregnancy and puberty.